DNA topoisomerase II (top2) is the cellular target of several among the most potent anticancer agents (doxorubicin, etoposide, mitoxanthrone). For this reason, it is one of the key targets in anticancer drug development. We have further demonstrated that two anthrapyrazoles derivatives in clinical trials for breast cancer are top2 inhibitors with a sequence selectivity comparable to that of mitoxantrone. We have also characterized a new top2 inhibitor that was found by Compare analysis of the NCI Anticancer Drug Screening Database. DNA topoisomerase I (top1) has become an essential target for anticancer research since the discovery that camptothecins are specific top1 poisons with promising anticancer activity. Our studies with an alkylating camptothecin derivative and with a camptothecin-resistant point mutant top1 have provided the most direct evidence that camptothecins block top1 by binding at the enzyme and therefore can induce DNA recombinations. This effect is relevant to the cytotoxicity of camptothecins and to the cellular functions of top1.